Indole-2-carboxamides and indole-2-carbonitriles are well known types of compounds and in recent years have been extensively reported as intermediates in the synthesis of 1,4-benzodiazepines. See, for example, Yamamoto et al., Chem. Ber., 101, pages 4245-4247 (1968); Inaba et al., Chem. Pharm. Bull., 19, pages 263-272 (1971); Inaba et al., Ibid, pages 722-729; Inaba et al., Chem. Pharm. Bull., 20, pages 1628-1636 (1972); Inaba et al., Chem. Pharm. Bull., 23, pages 3279-3282 (1975); Asami et al., Arzneim.-Forsch., 25, pages 534-539 (1975); Inaba et al., Chem. Pharm. Bull., 24, pages 1076-1082 (1976). These amides and nitriles are usually made from the corresponding esters and/or acids by standard procedures. However, problems are encountered when employing these standard procedures, in particular, lengthy and involved reaction steps resulting in intermediates which require separation and purification. Efficient use of these standard procedures is also impaired when the starting materials or intermediates contain functional groups which are reactive under the standard reaction conditions.
An object of this invention is to provide a simplified procedure for the preparation of indole-2-carboxamides and indole-2-carbonitriles.
Certain of the indoles disclosed herein have been found to possess blood-platelet aggregation inhibitory properties.
Blood platelets, sometimes referred to as thrombocytes, are anucleate cells which exist in large numbers in normal mammalian blood and form a vital part of the complex hemostatic mechanism. When blood vessels are injured and bleeding occurs, blood platelets adhere to subendothelial tissue in the damaged vessel wall and then clump or aggregate to form a platelet plug which arrests the bleeding. This platelet plug is then consolidated by the formation of a network of fibrin which results from activation of the blood clotting system. The pathological extension of the normal hemostatic platelet plug is called a thrombus. This may occur in vessels where the inner wall is injured and bleeding does not occur as, e.g., in atherosclerosis. During thrombus formation, emboli (consisting of platelet aggregates or particles of the more developed thrombus) may go downstream in the blood, lodge in small vessels to completely occlude them and block the flow of blood to a major organ. Thrombosis appears to play an important etiological role or complicating factor in a large number of disease states. While controversy continues as to the casual role of blood-platelet aggregation in atherosclerosis, it is accepted that such platelet aggregation accelerates the narrowing and eventual closure of the vascular lumen begun by the atherosclerotic plaque.
A factor which may be involved in these pathological (thrombocytopathic) phenomena is abnormal blood-platelet adhesiveness. Regardless of the mechanism, it is generally conceded that thrombosis plays a critical role in stroke, pulmonary embolism and myocardial infarction. It is generally believed that if this tendency toward undesired platelet aggregation or adhesiveness could be reduced, the incidence of thrombotic episodes would be reduced.
Certain prostaglandins, particularly those of the "E" series, such as (11,13E,15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid (PGE.sub.1), (8.beta.,11.alpha.,13E,15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid (8-iso-PGE.sub.1) and (11.alpha.,13E,15S)-11,15-dihydroxy-20-methyl-9-oxoprost-13-en-1-oic acid (.omega.-homo PGE.sub.1) have been demonstrated to inhibit platelet aggregation, Kloeze, Biochim. Biophys. Acta, 187, pages 285-292 (1969); and Serhar et al., Circulation, 38, Supp. 6, pages VI-23 (1968). However, while the above disclosed prostaglandins are known to possess platelet anti-aggregating properties, their use for preventing thrombosis has been seriously limited because their anti-aggregating properties are rapidly destroyed in the circulation during passage through the lungs by an enzyme (PG dehydrogenase) which converts the 15-OH function to a ketone. The administration of these prostaglandins is also associated with several undesirable side effects. Additionally, the prostaglandins of the "E" series readily undergo autooxidation to other forms of prostaglandins that lack platelet anti-aggregation properties: Shaw et al., Meth. Biochem. Anal., 17, pages 325-371 (1969). Thus, in view of this presentation, it becomes immediately apparent that a critical need exists for a method for inhibiting aggregation of platelets that is essentially free from the tribulations associated with the prior art. Likewise, it will be further apparent that if a new and useful method for protecting platelets is made available to the art, especially wherein the platelet anti-aggregation agent possesses stability, said method would have a positive medical value and it would also present a substantial contribution to the art.
Smith et al. in the Brit. J. Pharmacology, 40, pages 545P-546P (1970) demonstrated that human blood platelets can form and release prostaglandins PGE.sub.2 and PGF.sub.2.alpha. when the washed platelets are treated with thrombin. Silver et al. in Prostaglandins, 1, pages 429-436 (1972) showed that these prostaglandins were formed during blood clotting. They are also formed during the aggregation of platelets in platelet-rich plasma in response to collagen, epinephrine, adenosine diphosphate (ADP); Smith et al., J. Clin. Invest., 52, pages 965-969 (1973). The precursor of these prostaglandins is arachidonic acid ((all Z)-5,8,11,14-eicosatetraenoic acid). It has been shown that arachidonic acid induces both platelet aggregation and prostaglandin synthesis. During the bioconversion of arachidonic acid to PGE.sub.2, PGF.sub.2.alpha., and other polar products which occur in platelets, thromboxanes transiently accumulate. Thromboxanes induce platelet aggregation. Thromboxanes can also induce the release of aggregatory substances from stores within the platelet. The biological effects of thromboxanes are potentiated (up to .about.700%) in the presence of submicrogram concentrations of PGE.sub.2 ; Silver et al. Prostaglandins, 4, pages 863-875, (1973). That thromboxanes may be the causative factor in arterial thrombosis is based on the fact that aspirin, which has anti-thrombotic properties in laboratory animal models of arterial thrombosis, inhibits the biosynthesis of thromboxanes.
A further object of this invention is to provide a method of inhibiting or preventing blood-platelet aggregation by the use of certain indoles.